IL-22 in epithelial regeneration after allogeneic transplant

Summary

Principal Investigator: Alan Hanash
Abstract: DESCRIPTION (provided by applicant): Allogeneic hematopoietic transplantation is a curative therapy for numerous malignant and non-malignant he- matopoietic diseases that are otherwise incurable. Despite decades of intensive research, several major complications remain, including prolonged post-transplant immune deficiency and graft vs. host disease (GVHD). Gastrointestinal GVHD in particular is the predominant contributor to acute GVHD-related mortality, and dam- age to other target organs such as the thymus contributes significantly towards post-transplant immune deficiency. While much progress has been made toward understanding the immune response of the donor graft against the transplant recipient, there is little understanding of how transplant recipients respond to GVHD and its concomitant damage. Furthermore, virtually all strategies available to reduce clinical GVHD do so by limiting the donor immune system at the expense of therapeutic graft vs. leukemia/lymphoma (GVL) responses. IL-22 is a recently characterized cytokine that has been shown to protect intestinal epithelium during experimental inflammatory bowel disease. IL-22 receptor expression is restricted to non-hematopoietic cells, thus providing specificity to recipient epithelium in the transplant setting. Manipulation of this cytokine could there- fore protect epithelial tissues in transplant recipients without altering donor immunity or reducing GVL. Our preliminary data demonstrate that IL-22 is produced post-transplant by radio resistant host-derived innate lymphoid cells. These cells were eliminated during GVHD and deficiency if host-derived IL-22 led to increased GVHD morbidity, mortality, and pathology. Our data also indicate that the intestinal stem cells (ISC) necessary for nor- mal epithelial maintenance are targets of GVHD, and that IL-22 may be critical for the protection of these ISC during GVHD. Finally, our data indicate that IL-22 is critical for protecting the function of thyme epithelium post-transplant, an that IL-22 administration can eliminate thyme damage due to GVHD. We propose to test the hypothesis that IL-22 promotes survival and healing of damaged epithelium during allow- generic transplant. This project aims to: study the effects of IL-22 deficiency on GVHD and conditioning-related epithelial damage in experimental models, and study administration of IL-22 for reduction of post-transplant morbidity and mortality. Our ultimate goal is to develop a novel therapeutic strategy for prevention and treatment of GVHD. Potential therapeutic strategies will be tested in leukemia-bearing mice to ensure that GVL activity is preserved. We anticipate that these translational studies will not only lead to better understanding of immunobiology, intestinal stem cell physiology, epithelial regeneration, and GVHD pathophysiology, but will also lead to the development novel strategies to reduce epithelial damage post-transplant and improve the lives of transplant patients with both malignant and non-malignant hematopoietic disease. The specific aims are: 1: To study the effects of IL-22 deficiency on GVHD, conditioning-related damage, and post-transplant immune function. We will utilize a combination of IL-22 KO mice and IL-22 neutralizing antibody to assess the role of IL- 22 in target tissues and cells. 2: To study administration of IL-22 for reduction of post-transplant tissue damage and augmentation of post- transplant immunity. We will treat transplants recipients with systemic short-acting recombinant IL-22, induce constitutive IL-22 with an engineered expression vector, and administer IL-22 with intermediate-duration IL-22- loaded nanoparticles to test therapeutic administration strategies. The applicant, Dr. Alan Hanash, a medical oncology fellow at Memorial Sloan-Kettering Cancer Center (MSKCC) has outlined a five-year career plan that will build upon his background in immunology and clinical oncology/malignant hematology. Under the mentorship of Dr. Marcel van den Brink, a recognized leader in transplant immunology, GVHD, and immune reconstitution post-transplant, Dr. Hanash will utilize translational in vivo pre-clinical models with a combination of genetic deficiencies and cytokine administration approaches to study the role of IL-22 in reducing tissue damage and augmenting immune function after allogeneic transplant. Dr. Hanash will be mentored by an Advisory Committee of internationally recognized experts in the field. Finally, this plan is ideally carried out in the Department of Medicine and Program in Immunology at MSKCC, given its distinguished record for training physician-scientists in a rich and collaborative environment. With the support provided by the K08 award, Dr. Hanash's project will lead to the development of novel biologic insights into the relationship between lymphoid cells and stromal maintenance, as well as clinically effective strategies for promoting this maintenance during inflammatory tissue damage. In addition, the career development goal of this project is to help Dr. Hanash transition into an independent investigator with his own laboratory and R01 funding.
Funding Period: 2012-09-01 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease
    Alan M Hanash
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Immunity 37:339-50. 2012

Research Grants

  1. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
  2. New Mexico HPV Outcomes, Practice Effectiveness and Surveillance (NM-HOPES)
    Cosette Marie Wheeler; Fiscal Year: 2013
  3. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
  4. Martin Delaney Collaboratory to Eradicate HIV-1 Infection
    David M Margolis; Fiscal Year: 2013
  5. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
  6. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
  7. Biology &Transplantation of the Human Stem Cell
    John E Wagner; Fiscal Year: 2013
  8. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
  9. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
  10. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease
    Alan M Hanash
    Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Immunity 37:339-50. 2012
    ..Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage...

Research Grants41

  1. P53 - REGULATORS AND EFFECTORS
    Stuart A Aaronson; Fiscal Year: 2013
    ..This Program brings together a senior group of investigators from different disciplines and with complementary expertise focused on important and novel aspects of p53 biology. ..
  2. New Mexico HPV Outcomes, Practice Effectiveness and Surveillance (NM-HOPES)
    Cosette Marie Wheeler; Fiscal Year: 2013
    ....
  3. Center for Interdisciplinary Research on Nicotine Addiction (CIRNA)
    Caryn Lerman; Fiscal Year: 2013
    ..The CIRNA is proposed to replace the TTURC, since this NIH initiative is ending. ..
  4. Martin Delaney Collaboratory to Eradicate HIV-1 Infection
    David M Margolis; Fiscal Year: 2013
    ..We are convinced that together we will catalyze advances that will ultimately lead to the eradication of HIV infection. ..
  5. Host Defense Against HIV-related Pulmonary Infections
    Judd E Shellito; Fiscal Year: 2013
    ..abstract_text> ..
  6. Epidemiology of Breast Cancer Subtypes in African American Women: a Consortium
    Julie R Palmer; Fiscal Year: 2013
    ..By pooling our data, specimens, and importantly, expertise to investigate these synergist hypotheses, we will elucidate much of the etiology of aggressive, early onset breast cancers in AA women. ..
  7. Biology &Transplantation of the Human Stem Cell
    John E Wagner; Fiscal Year: 2013
    ..abstract_text> ..
  8. Mayo SPORE in Brain Cancer
    BRIAN PATRICK O'NEILL; Fiscal Year: 2013
    ..D.) D. Animal Core (Director: J.N. Sarkaria, M.D.;Co-Director: I.F. Parney, M.D., Ph.D.) E. Clinical Research Core (Director: J.C. Buckner, M.D.;Co-Director: D. H. Lachance, M.D.) Developmental Research Portfolio ..
  9. Center for Narcolepsy and Related Disorders (P50)
    Emmanuel J Mignot; Fiscal Year: 2013
    ..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
  10. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
    ..The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight. ..
  11. Signaling in Inflammation, Stress, and Tumorigenesis
    GEORGE ROBERT STARK; Fiscal Year: 2013
    ..abstract_text> ..
  12. MIXED HEMATOPOIETIC CHIMERISM AFTER STEM CELL ALLOGRAFTS
    Rainer F Storb; Fiscal Year: 2013
    ..This is especially important since median ages at diagnosis of patients with most candidate diseases range from 65 to 70 years, which is beyond the age range of inclusion in conventional myeloablative HCT regimens. ..
  13. STEM CELL GENE THERAPY FOR HEMOGLOBINOPATHIES
    George Stamatoyannopoulos; Fiscal Year: 2013
    ..The focus of this Program Project, Gene Therapy, can provide a new paradigm for the treatment of these hemoglobinopathies as well as for other blood diseases. (End of Abstract) ..
  14. MOLECULAR BASIS OF VIRAL AND CELLULAR TRANSFORMATION
    DANIEL C DIMAIO; Fiscal Year: 2013
    ..abstract_text> ..
  15. IL-22 in Thymic Regeneration
    Marcel R m van den Brink; Fiscal Year: 2013
    ....
  16. Immuno/Immuno-Gene Therapies for Thoracic Malignancies
    STEVEN MARK ALBELDA; Fiscal Year: 2013
    ..Core C will provide biostatistical and data management services. The goal of this P01 is to alter the treatment paradigm for MPM and advance the entire field of adoptive T cell transfer. ..
  17. Investigating the role of interleukin-22 in thymus function
    Jarrod Dudakov; Fiscal Year: 2013
    ....
  18. Radiation Bystander Effects: Mechanisms
    Tom K Hei; Fiscal Year: 2013
    ..abstract_text> ..
  19. Role of the thymic epithelium on the outcome of allogeneic transplantation
    Konstantina Alexandropoulos; Fiscal Year: 2013
    ....
  20. Mucosal Immunity and Microbiota in Intestinal Graft-versus-Host Disease
    Marcel R m van den Brink; Fiscal Year: 2013
    ..Therefore, we expect that these preclinical studies have a high likelihood to improve prophylaxis and treatment of intestinal GVHD as well as overall outcome in allo BMT patients. ..
  21. Herpesviral, Oncogenesis, Latency and Reactivation
    NANCY JOAN RAAB-TRAUB; Fiscal Year: 2013
    ..abstract_text> ..
  22. Therapeutic Opportunities for Pediatric Astrocytoma
    Rosalind A Segal; Fiscal Year: 2013
    ..The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core. ..